Journal of Medicinal Chemistry p. 4979 - 4990 (2019)
Update date:2022-08-15
Topics:
Wang, Zhen
Jiang, Xiangrui
Zhang, Xianglei
Tian, Guanghui
Yang, Rulei
Wu, Jianzhong
Zou, Xiaoli
Liu, Zheng
Yang, Xiaojun
Wu, Chunhui
Shi, Jing
Li, Jianfeng
Suo, Jin
Wang, Yu
Zhang, Rongxia
Xu, Zhijian
Gong, Xudong
He, Yang
Zhu, Weiliang
Aisa, Haji Akber
Jiang, Hualiang
Xu, Yechun
Shen, Jingshan
Phosphodiesterase type 5 (PDE5) inhibitors are first-line therapy for pulmonary arterial hypertension (PAH) and erectile dysfunction. As a continuing work to improve the terminal half-lives and oral bioavailabilities of our previously reported 4(3H)-pyrimidones, a pharmacokinetics-driven optimization focusing on the terminal substituent is described. Two major congeneric series of 4(3H)-pyrimidones, the aminosulfonylphenylpyrimidones and acylaminophenylpyrimidones, were designed, synthesized, and pharmacologically assessed in vitro and in vivo. Among them, compound 15 (TPN171) with subnanomolar potency for PDE5 and good selectivity over PDE6 was finally recognized as a potential drug candidate, and its pharmacokinetic profiles in rats and dogs are significantly improved compared to the starting compound (3). Moreover, TPN171 was proven to exert a longer lasting effect than sildenafil in animal models, providing a foundation for a once-daily oral administration for its clinical use. TPN171 is currently being investigated in a phase II clinical trial for the treatment of PAH.
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